肿瘤干细胞DC疫苗与抗PD-L1抗体联用抗结肠癌的实验研究
发布时间：2018-10-12 09:26
【摘要】：目的:结肠癌作为常见的消化道恶性肿瘤,在我国的发病率和死亡率均呈逐年上升趋势。结肠癌由于术后易复发,放化疗耐受等特点,目前临床上的治疗效果都不理想。因此,需要探索出新的结肠癌治疗策略。肿瘤干细胞(cancer stem cells,CSCs)是肿瘤组织中存在的较少的具有自我更新能力并能无限增殖、多向分化并对放化疗不敏感的细胞亚群,与肿瘤的发生、发展和各种生物学抗性密切相关。肿瘤干细胞理论的提出使人们认识到,以肿瘤干细胞为靶点的抗肿瘤治疗策略为彻底治愈肿瘤带来了可能。树突状细胞(dendritic cell,DC)是目前已知的生物体内功能最强的专职抗原提呈细胞(antigen presenting cell,APC),能够特异性地诱导机体免疫应答的发生。PD-L1作为负性免疫共刺激分子在肿瘤免疫逃逸过程中起到重要作用,抗PD-L1单抗能与肿瘤微环境中表达的PD-L1相结合,减弱PD-L1介导的免疫逃逸作用,从而增强DC疫苗介导的的免疫治疗效果。因此,本实验以CD44作为分选标志物,从小鼠结肠癌细胞系CT-26分选出CD44+细胞作为小鼠肿瘤干细胞,拟将CD44+CT-26细胞完全抗原致敏的DC疫苗与抗PD-L1单抗联用,探讨这种联合治疗策略能否有效地治疗小鼠结肠癌,为结肠癌靶向治疗提供实验依据。方法:免疫磁珠法分选获得CD44+CT-26细胞,用含20 ng/ml EGF、20 ng/ml b FGF、2%B27的DMEM/F12无血清肿瘤干细胞培养基培养;从小鼠骨髓中获得DC,将CT-26细胞裂解物和CD44+CT-26细胞裂解物分别作为抗原负载DC,获得DCCT-26和DCSC疫苗;然后,分别与抗PD-L1单抗联用,进行结肠癌荷瘤小鼠免疫治疗实验。分析小鼠的生存状态,肿瘤生长情况,小鼠脾来源T细胞对结肠癌细胞的杀伤作用。结果:(1)与Control组和αPD-L1组相比,DCSC+αPD-L1组小鼠的肿瘤生长显著受到抑制(P0.05);肿瘤重量显著减小(P0.05);小鼠脾来源CTL对CT-26细胞的杀伤显著增强(P0.05)。(2)与DCSC组相比,除小鼠脾来源CTL对CT-26细胞的杀伤显著增强(P0.05)外,DCSC+αPD-L1组与DCSC组其他指标无显著性差异。(3)与DCCT-26组相比,除小鼠肿瘤重量显著减小(P0.05)外,DCSC组与DCCT-26组其他指标无显著性差异。(4)与DCCT-26+αPD-L1组相比,DCSC+αPD-L1组与DCCT-26+αPD-L1组其他指标无显著性差异。结论:在BALB/c小鼠结肠癌模型中,CD44+CT26细胞完全抗原负载的DC疫苗与抗PD-L1单抗联用可以产生有效地抗肿瘤免疫治疗效果,抑制肿瘤生长,增强对肿瘤细胞的杀伤效果。但是与肿瘤细胞抗原致敏的DC疫苗相比,抗肿瘤免疫治疗优势不明显。
[Abstract]:%E7%9B%AE%E7%9A%84%3A%E7%BB%93%E8%82%A0%E7%99%8C%E4%BD%9C%E4%B8%BA%E5%B8%B8%E8%A7%81%E7%9A%84%E6%B6%88%E5%8C%96%E9%81%93%E6%81%B6%E6%80%A7%E8%82%BF%E7%98%A4%2C%E5%9C%A8%E6%88%91%E5%9B%BD%E7%9A%84%E5%8F%91%E7%97%85%E7%8E%87%E5%92%8C%E6%AD%BB%E4%BA%A1%E7%8E%87%E5%9D%87%E5%91%88%E9%80%90%E5%B9%B4%E4%B8%8A%E5%8D%87%E8%B6%8B%E5%8A%BF.%E7%BB%93%E8%82%A0%E7%99%8C%E7%94%B1%E4%BA%8E%E6%9C%AF%E5%90%8E%E6%98%93%E5%A4%8D%E5%8F%91%2C%E6%94%BE%E5%8C%96%E7%96%97%E8%80%90%E5%8F%97%E7%AD%89%E7%89%B9%E7%82%B9%2C%E7%9B%AE%E5%89%8D%E4%B8%B4%E5%BA%8A%E4%B8%8A%E7%9A%84%E6%B2%BB%E7%96%97%E6%95%88%E6%9E%9C%E9%83%BD%E4%B8%8D%E7%90%86%E6%83%B3.%E5%9B%A0%E6%AD%A4%2C%E9%9C%80%E8%A6%81%E6%8E%A2%E7%B4%A2%E5%87%BA%E6%96%B0%E7%9A%84%E7%BB%93%E8%82%A0%E7%99%8C%E6%B2%BB%E7%96%97%E7%AD%96%E7%95%A5.%E8%82%BF%E7%98%A4%E5%B9%B2%E7%BB%86%E8%83%9E%28cancer%20stem%20cells%2CCSCs%29%E6%98%AF%E8%82%BF%E7%98%A4%E7%BB%84%E7%BB%87%E4%B8%AD%E5%AD%98%E5%9C%A8%E7%9A%84%E8%BE%83%E5%B0%91%E7%9A%84%E5%85%B7%E6%9C%89%E8%87%AA%E6%88%91%E6%9B%B4%E6%96%B0%E8%83%BD%E5%8A%9B%E5%B9%B6%E8%83%BD%E6%97%A0%E9%99%90%E5%A2%9E%E6%AE%96%2C%E5%A4%9A%E5%90%91%E5%88%86%E5%8C%96%E5%B9%B6%E5%AF%B9%E6%94%BE%E5%8C%96%E7%96%97%E4%B8%8D%E6%95%8F%E6%84%9F%E7%9A%84%E7%BB%86%E8%83%9E%E4%BA%9A%E7%BE%A4%2C%E4%B8%8E%E8%82%BF%E7%98%A4%E7%9A%84%E5%8F%91%E7%94%9F%2C%E5%8F%91%E5%B1%95%E5%92%8C%E5%90%84%E7%A7%8D%E7%94%9F%E7%89%A9%E5%AD%A6%E6%8A%97%E6%80%A7%E5%AF%86%E5%88%87%E7%9B%B8%E5%85%B3.%E8%82%BF%E7%98%A4%E5%B9%B2%E7%BB%86%E8%83%9E%E7%90%86%E8%AE%BA%E7%9A%84%E6%8F%90%E5%87%BA%E4%BD%BF%E4%BA%BA%E4%BB%AC%E8%AE%A4%E8%AF%86%E5%88%B0%2C%E4%BB%A5%E8%82%BF%E7%98%A4%E5%B9%B2%E7%BB%86%E8%83%9E%E4%B8%BA%E9%9D%B6%E7%82%B9%E7%9A%84%E6%8A%97%E8%82%BF%E7%98%A4%E6%B2%BB%E7%96%97%E7%AD%96%E7%95%A5%E4%B8%BA%E5%BD%BB%E5%BA%95%E6%B2%BB%E6%84%88%E8%82%BF%E7%98%A4%E5%B8%A6%E6%9D%A5%E4%BA%86%E5%8F%AF%E8%83%BD.%E6%A0%91%E7%AA%81%E7%8A%B6%E7%BB%86%E8%83%9E%28dendritic%20cell%2CDC%29%E6%98%AF%E7%9B%AE%E5%89%8D%E5%B7%B2%E7%9F%A5%E7%9A%84%E7%94%9F%E7%89%A9%E4%BD%93%E5%86%85%E5%8A%9F%E8%83%BD%E6%9C%80%E5%BC%BA%E7%9A%84%E4%B8%93%E8%81%8C%E6%8A%97%E5%8E%9F%E6%8F%90%E5%91%88%E7%BB%86%E8%83%9E%28antigen%20presenting%20cell%2CAPC%29%2C%E8%83%BD%E5%A4%9F%E7%89%B9%E5%BC%82%E6%80%A7%E5%9C%B0%E8%AF%B1%E5%AF%BC%E6%9C%BA%E4%BD%93%E5%85%8D%E7%96%AB%E5%BA%94%E7%AD%94%E7%9A%84%E5%8F%91%E7%94%9F.PD-L1%E4%BD%9C%E4%B8%BA%E8%B4%9F%E6%80%A7%E5%85%8D%E7%96%AB%E5%85%B1%E5%88%BA%E6%BF%80%E5%88%86%E5%AD%90%E5%9C%A8%E8%82%BF%E7%98%A4%E5%85%8D%E7%96%AB%E9%80%83%E9%80%B8%E8%BF%87%E7%A8%8B%E4%B8%AD%E8%B5%B7%E5%88%B0%E9%87%8D%E8%A6%81%E4%BD%9C%E7%94%A8%2C%E6%8A%97PD-L1%E5%8D%95%E6%8A%97%E8%83%BD%E4%B8%8E%E8%82%BF%E7%98%A4%E5%BE%AE%E7%8E%AF%E5%A2%83%E4%B8%AD%E8%A1%A8%E8%BE%BE%E7%9A%84PD-L1%E7%9B%B8%E7%BB%93%E5%90%88%2C%E5%87%8F%E5%BC%B1PD-L1%E4%BB%8B%E5%AF%BC%E7%9A%84%E5%85%8D%E7%96%AB%E9%80%83%E9%80%B8%E4%BD%9C%E7%94%A8%2C%E4%BB%8E%E8%80%8C%E5%A2%9E%E5%BC%BADC%E7%96%AB%E8%8B%97%E4%BB%8B%E5%AF%BC%E7%9A%84%E7%9A%84%E5%85%8D%E7%96%AB%E6%B2%BB%E7%96%97%E6%95%88%E6%9E%9C.%E5%9B%A0%E6%AD%A4%2C%E6%9C%AC%E5%AE%9E%E9%AA%8C%E4%BB%A5CD44%E4%BD%9C%E4%B8%BA%E5%88%86%E9%80%89%E6%A0%87%E5%BF%97%E7%89%A9%2C%E4%BB%8E%E5%B0%8F%E9%BC%A0%E7%BB%93%E8%82%A0%E7%99%8C%E7%BB%86%E8%83%9E%E7%B3%BBCT-26%E5%88%86%E9%80%89%E5%87%BACD44%20%E7%BB%86%E8%83%9E%E4%BD%9C%E4%B8%BA%E5%B0%8F%E9%BC%A0%E8%82%BF%E7%98%A4%E5%B9%B2%E7%BB%86%E8%83%9E%2C%E6%8B%9F%E5%B0%86CD44%20CT-26%E7%BB%86%E8%83%9E%E5%AE%8C%E5%85%A8%E6%8A%97%E5%8E%9F%E8%87%B4%E6%95%8F%E7%9A%84DC%E7%96%AB%E8%8B%97%E4%B8%8E%E6%8A%97PD-L1%E5%8D%95%E6%8A%97%E8%81%94%E7%94%A8%2C%E6%8E%A2%E8%AE%A8%E8%BF%99%E7%A7%8D%E8%81%94%E5%90%88%E6%B2%BB%E7%96%97%E7%AD%96%E7%95%A5%E8%83%BD%E5%90%A6%E6%9C%89%E6%95%88%E5%9C%B0%E6%B2%BB%E7%96%97%E5%B0%8F%E9%BC%A0%E7%BB%93%E8%82%A0%E7%99%8C%2C%E4%B8%BA%E7%BB%93%E8%82%A0%E7%99%8C%E9%9D%B6%E5%90%91%E6%B2%BB%E7%96%97%E6%8F%90%E4%BE%9B%E5%AE%9E%E9%AA%8C%E4%BE%9D%E6%8D%AE.%E6%96%B9%E6%B3%95%3A%E5%85%8D%E7%96%AB%E7%A3%81%E7%8F%A0%E6%B3%95%E5%88%86%E9%80%89%E8%8E%B7%E5%BE%97CD44%20CT-26%E7%BB%86%E8%83%9E%2C%E7%94%A8%E5%90%AB20%20ng%2Fml%20EGF%2C20%20ng%2Fml%20b%20FGF%2C2%B27%E7%9A%84DMEM%2FF12%E6%97%A0%E8%A1%80%E6%B8%85%E8%82%BF%E7%98%A4%E5%B9%B2%E7%BB%86%E8%83%9E%E5%9F%B9%E5%85%BB%E5%9F%BA%E5%9F%B9%E5%85%BB%3B%E4%BB%8E%E5%B0%8F%E9%BC%A0%E9%AA%A8%E9%AB%93%E4%B8%AD%E8%8E%B7%E5%BE%97DC%2C%E5%B0%86CT-26%E7%BB%86%E8%83%9E%E8%A3%82%E8%A7%A3%E7%89%A9%E5%92%8CCD44%20CT-26%E7%BB%86%E8%83%9E%E8%A3%82%E8%A7%A3%E7%89%A9%E5%88%86%E5%88%AB%E4%BD%9C%E4%B8%BA%E6%8A%97%E5%8E%9F%E8%B4%9F%E8%BD%BDDC%2C%E8%8E%B7%E5%BE%97DCCT-26%E5%92%8CDCSC%E7%96%AB%E8%8B%97%3B%E7%84%B6%E5%90%8E%2C%E5%88%86%E5%88%AB%E4%B8%8E%E6%8A%97PD-L1%E5%8D%95%E6%8A%97%E8%81%94%E7%94%A8%2C%E8%BF%9B%E8%A1%8C%E7%BB%93%E8%82%A0%E7%99%8C%E8%8D%B7%E7%98%A4%E5%B0%8F%E9%BC%A0%E5%85%8D%E7%96%AB%E6%B2%BB%E7%96%97%E5%AE%9E%E9%AA%8C.%E5%88%86%E6%9E%90%E5%B0%8F%E9%BC%A0%E7%9A%84%E7%94%9F%E5%AD%98%E7%8A%B6%E6%80%81%2C%E8%82%BF%E7%98%A4%E7%94%9F%E9%95%BF%E6%83%85%E5%86%B5%2C%E5%B0%8F%E9%BC%A0%E8%84%BE%E6%9D%A5%E6%BA%90T%E7%BB%86%E8%83%9E%E5%AF%B9%E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【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.35
本文编号：2265614
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【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.35
【参考文献】
相关期刊论文 前5条
1 Wanqing Chen;Rongshou Zheng;Tingting Zuo;Hongmei Zeng;Siwei Zhang;Jie He;;National cancer incidence and mortality in China, 2012[J];Chinese Journal of Cancer Research;2016年01期
2 刘见荣;侯风刚;;结肠癌治疗概况[J];辽宁中医药大学学报;2014年02期
3 陈琼;刘志才;程兰平;宋国慧;孙喜斌;郑荣寿;张思维;陈万青;;2003～2007年中国结直肠癌发病与死亡分析[J];中国肿瘤;2012年03期
4 Mabood Qureshi;Jim Xiang;;Dendritic Cell-Derived Exosomes Stimulate Stronger CD8~+ CTL Responses and Antitumor Immunity than TVimor Cell-Derived Exosomes[J];Cellular & Molecular Immunology;2006年03期
5 王正康;黄莛庭;;结肠癌根治术的合理切除范围(文献综述)[J];国外医学.外科学分册;1989年01期
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